We have investigated the expression of the c-raf-1 proto-oncogene in neoplastic as well as hyperplastic pathologies. All small cell lung carcinomas examined express elevated levels of raf transcripts, this was particularly true of non-cultured metastases. Characterization of other surface markers revealed the presence of early monomyelocyte antigens, suggesting that these cells may have evolved from hemopoietic precursors. Activated T and B cells obtained from the peripheral blood of human autoimmune diseased individuals or from lymph nodes and spleens isolated from autoimmune mice, also expressed elevated levels of the raf proto-oncogene transcript. A human fetal liver cDNA library was screened at reduced stringency for v-raf related sequences. In addition to the expected c-raf-1 cDNA a novel sequence was isolated. Comparison of the new gene (c-pks-1) to the other raf homologs revealed nucleotide homolgies of 71%. The expression of c-pks-1 mRNA (2.8-Kb) is elevated in peripheral blood mononuclear cells isolated from patients with systemic lupus erythematosus and angioimmunoblastic lymphadenopathy with dysproteinema (AILD). In the course of localizing the c-pks-1 gene to the short arm of the X chromosome (Xpter-Xp11), another related gene (c-pks-2) was recognized and localized to chromosome 7 (7pter-7q22). The yeast homolog of raf has been cloned into Lambdagt 10 and subcloned into pBR322. Sequencing and expression studies are planned.